Amides of podophyllic acid and picropodophyllic acid



AlVlIDES OF PODOPHYLLIC ACID AND PICROPODOPHYLLIC ACID Jiirg Rutschmann, berwil/Bld., Switzerland, assignor to A. G. Sandoz, Basel, Switzerland, a Swiss firm No Drawing. Original application June 2, 1958, Ser- No. 739,009. Divided and this application June 21, 1960, Ser. No. 37,591

2 Claims. (Cl. 260-3405) in which R is either trans C epimer of podophyllic acid having the molecular formula C H O or the C epimer having the cis structure, i.e., picropodophyllic acid of molecular formula C H O UTILITY The foregoing podophyllic acid amides of the invention are distinguished therapeutically from the lactones from which they originate in that they exhibit very low toxicity and this constitutes their main advantage over the toxic podophyllotoxin and picropodophyllin.

The characteristics of podophyllin are given at page 1052 of the text by Goodman and Gilman, The Pharmacological Basis of Therapeutics, second edition (MacMillan 1955).

As in the case of podophyllin, the compounds of the invention have further utility in the treatment of condyl- 40 oma acuminata but have the additional advantage of lower toxicity whereas podophyllin is quite toxic.

As stated in the text by Goodman & Gilman referred to hereinabove, the podophyllum resin presumably exerts its cathartic effect by an irritant, cytotoxic action on 45 the intestinal tract and small amounts (up to milligrams) produce copious, soft stools within 12 to 24 hours. Beyond 5 milligrams, the cytotoxic properties of the resin are clearly seen: the stool becomes very watery and may become bloody. Podophyllin is uncertain in its action, and a mild dose for one individual may purge another severely. Furthermore, its high systemic toxicity and general cytotoxic action preclude its safe employment as a cathartic.

The above disadvantages are eliminated by the compounds of the invention which act as mild laxatives or cathartics. The laxative action can be controlled by appropriate dosage of the order of milligrams and does not lead to uncontrollable diarrhea as observed in the instances where podophyllotoxin is used or where podophyllum resin U.S.P. is used.

The discovery that the foregoing amide compounds of the invention eliminate the severe purgative characteristics of podophyllin as well as its high systemic toxicity permits the utilization of these podophyllic acid derivatives of the invention as improved cathartics.

THE C PICROPODOPHYLLIN EPIMER It is known that odophyllotoxin shows an antimitotic eifect. See M. G. Kelly and l. L. Hartwell, J. Nat. Canoer Inst, 14, 967 (1954). It is also known that picropodophyllin (H), a product of the reaction of podophyllotoxin with weak alkalis I on onto -oon| 0 H3 n on 0 l "i o g 00 CHsO- -OCH: 25

OCHa

is effective as an anti-mitotic agent The reaction is, therefore, merely of chemical interest.

Podophyllotoxin and picropodophyllin show the relationship of diastereo-isomers respectively due to epimerism at the C position. The lactone group of podophyllotoxin is trans located while the lactone group is picropodophyllin is cis located.

The toxicity of the podophyllotoxin groups is of great significance in therapeutical use. In the case of podophyllotoxin itself, the relationship of effectiveness and toxicity is so unfavorable that there has been no possibility for practical use. For example, as stated in the Goodman & Gilman text at page 1052.

FORMATION OF HYDRAZIDES The readily obtainable starting material for the reaction according to the invention, i.e. the hydrazides of Formulas III and IV hereinbelow:

III OH CHzOH on, I 0 --C O-NH-NH! CH|O O CH:

6GB: IV OH CHaOH CH:

CO--NHNH1 Q in.

SE30 0 CH:

may be obtained from the two corresponding lactones, the 7 natural odophyllotoxin and its C epimer picropodophyllin, the product of reaction with an alkali and splitting of the lactone ring with hydrazine. This reaction has been 3 carried out by W. Borsche and J. Niemann (Ann. Chem, 499, 59-1932) whereby a so-called podophyllic acid hydrazide was obtained from the two lactones as the only product resulting from the reaction.

Thorough examination of this reaction reveals that by splitting the picropodophyllin with hydrazine, a compound is produced with nearly the same characteristics as those described by Borsche and Niemann in substantially quantitative yield. This compound is labelled in the following description as picropodophyllic acid hydrazide IV because of its stereochemical relation.

Compound IV can also be obtained by treating podophyllotoxin with hydrazine whereby the lactone epimerizes under alkaline conditions during the reaction and forms picropodophyllin.

In addition to the corresponding hydrazide IV, a second stereoisomeric hydrazide III is found and this compound is obtained from the podophyllotoxin without epimerization. It has been found that stereoisomeric product III is practically the only product obtained if the hydrazine splitting of the podophyllotoxin is carried out in the presence of an acid buffer in an amount to reduce the alkalinity of the reaction medium and to thereby diminish the rearrangement of the podophyllotoxin configuration into the epimeric picropodophyllin configuration. A preferred method for this type of splitting employs acetic acid as a buffer. Verification of the assumptions regarding the stereo-chemistry of the two hydrazides was demonstrated by transformation of the hydrazides back into the original lactones.

FORMATION OF PODOPHYLLIC ACID AMIDES To arrive at the new amide having the general formula R-NH in which R represents the radical C H O of the stercoisomeric podophyllic and picropodophyllic acid,

time being dependent on the temperature employed. If ethanol is used at boiling point, the reaction is finished after one or two hours. Since Raney-nickel often contains alkali from its preparation, which could disturb the hydrolysis-sensitive hydrazides, it is desirable to work in the presence of a neutralizing agent. For this purpose, acetic acid ethyl ester may be added to the solvent which will be immediately transformed into the alkali acetate through reaction with the free alkali. It is unexpected that this known reaction (C. Ainsworth, J. American Chemical Society, 76, 5774, 1954; 78, 1636, 1956) could be applied in the case of the hydrazides since experience shows that in similar reactions of the podophyllotoxin 4 series under the required conditions, there is a danger that a lactone ring may form, splitting off hydrazine.

The pronounced pharmacological effect of the new amide compounds is connected with a toxicity which is considerably less than that of podophyllin. Since the high toxicity of podophyllotoxin has rendered it useless for clinical application, the new amides of the podophyllic acids and of the picropodophyllic acids gain great significance.

The new derivatives of the podophyllic and picropodophyllic acids, produced in accordance with the present invention, crystallize at room temperature. They are intended for therapeutic use but are also suitable as intermediate products.

The following examples illustrate the invention:

Example I A solution of 1 gram of podophyllic acid hydrazide with 2.5 grams of freshly prepared Raney-nickel in 25 cubic centimeters of ethanol and 5 cubic centimeters of acetic acid ethyl ester was heated for two hours at reflux to the boiling point. The solution was filtered off the Raney-nickel and concentrated to a small volume. The podophyllic acid amide crystallized after cooling and had 5 a melting point of 20S-206 C. [al =213 (c.=0.4

in ethanol).

Example II References Cited in the file of this patent UNITED STATES PATENTS Yale et al Mar. 25. 1958 OTHER REFERENCES Borsche et al.: Ann. Chem, vol. 499, page 76 (1932). Ainsworth: I. Am. Chem. Society, vol. 76-page 5774 (1954). 

1. PODOPHYLLIC ACID AMIDE. 